Method and apparatus for measuring intravascular blood flow using a backscattering contrast

This application is based on, claims the benefit of, and claims priority to U.S. Provisional Application No. 62/659,773, filed Apr. 19, 2018, which is hereby incorporated herein by reference in its entirety for all purposes.

This invention was made with government support under K25 EB024595 and P41 EB015903 awarded by the National Institutes of Health. The government has certain rights in the invention.

This invention relates generally to determinations of flow rates, and more particularly to methods and apparatus for determining intravascular flow rates based on velocity measurements obtained using backscattering contrast as measured by optical and/or ultrasonic methods.

Intravascular blood flow measurements have been challenging to obtain because of the difficulties in gaining access to the blood vessels where flow measurements are of interest. Among the most important targets are the coronary arteries, where blockages, called stenosis, can produce acute myocardial infarction, the leading cause of death in the developed world. Accurate intravascular blood flow measurements can only be acquired through the use of invasive measures because of the small size of the vessels of interest (at most a few millimeters in diameter), their location inside the body, and their complex three-dimensional structure.

Intravascular Doppler ultrasound (D-US) catheters have been developed for this purpose. However, D-US is only directly sensitive to movement in the line of sight (LOS). This represents a major drawback for accurate flow measurements, because the angle of the D-US probe inside the blood vessel is generally unknown and changes dynamically with heartbeat-induced motion. Although D-US in the Power Doppler modality is known to be sensitive to flow in all directions, there is not a known relationship between the Power Doppler reading and specific flow velocities. Usage of the Doppler Effect in optical technologies, such as optical coherence tomography, suffers from the same problems.

For reasons such as those discussed above, usage of intravascular D-US in the clinical environment has been limited. Other techniques that do not have the limitations of intravascular D-US have largely displaced its use. Among these are thermodilution techniques. Thermodilution uses the indicator-dilution framework to derive flow rates or flow velocities, where the contrast medium is a liquid at a different (generally lower) temperature that is mixed with blood at an injection site. This is the principle used in thermodilution coronary flow reserve (thermo-CFR) measurements, where the transit time of a bolus of saline at a temperature lower than circulating blood is measured using a catheter provided with a temperature transducer. Thermo-CFR cannot determine the blood flow rate, only a quantity proportional to blood flow rate. Because CFR is based on the ratio of the blood flow rate under vasodilation to blood flow rate at baseline conditions, the ratio of the transit times provides a CFR metric without the need to determine the unknown proportionality constant. However, this constant is dependent on the location of the temperature transducer and the vessel lumen area. Both quantities are expected to change, the former due to heartbeat motion, and the latter due to the lumen change under vasodilation.

Continuous thermodilution (cont-thermo) is a modification of the thermo-CFR technique in which the injectate is continuously mixed with the flowing blood at a fixed flow rate. Although cont-thermo is able to determine the blood flow rate, it can only do so under the specific conditions of the continuous saline injection. It has been shown that a continuous injection of saline, relevant for accurate measurements, produces a variable degree of vasodilation in the vessel of interest. Although this has been used to measure blood flow under vasodilation conditions, it inhibits an accurate measurement at baseline conditions and therefore cannot be used to determine an accurate CFR metric.

Finally, thermodilution techniques do not provide structural information (e.g. as is provided by imaging) about the vessels. In clinical practice imaging is highly desirable to directly assess the appearance of a given stenosis, which provides information about its vulnerability and therefore facilitates appropriate treatment. The cont-thermo catheter in particular is too large to allow an imaging catheter to be present in the vessel at the same time.

Thus, it would be desirable to have a system and a technique that overcomes one or more of the drawbacks discussed above, such as the limitations of Doppler techniques, the lack of reliable CFR measurements, and/or the limitations of continuous thermodilution, and which preferably enables intravascular imaging using the same instrumentation.

Exemplary embodiments according to the present disclosure can be provided to determine flow velocities and flow rates accurately while enabling intravascular imaging, which overcome the limitations of the techniques known in the art described above.

In one exemplary embodiment, the imaging system can be configured as an optical coherence tomography (“OCT”) or optical frequency-domain imaging (“OFDI”) system which performs cross-sectional imaging of a first fluid such as blood in a vessel such as a blood vessel. Furthermore the imaging system can be implemented in the time-domain or in the frequency-domain by means of a spectroscopic analyzer or a wavelength-swept source. This system can perform multidimensional imaging by optical or mechanical means to acquire one-, two-, or three-dimensional imaging of the sample as a function of time. In this exemplary embodiment the first fluid can be optically coupled to the imaging system in order to collect the light scattered from the first fluid and to produce interference between reflected light and reference light, producing interferometric signals that are collected by a detector. In the present exemplary embodiment, the imaging system can be configured to deliver a second fluid (such as saline solution) having different light scattering properties into the flow of the first fluid. In the present exemplary embodiment, the imaging system can be further configured to perform an analysis of the scattered light to determine the flow velocity of the first fluid.

In another exemplary embodiment, the imaging system can be fitted to a medical catheter configured to deliver radiation that may be scattered by the first, second, or more fluids. In this exemplary embodiment, the imaging system can deliver the second fluid with different light scattering properties into the flow of the first fluid. In this exemplary embodiment, the imaging system can be a one-dimensional OCT or OFDI system that implements a scanning probe in one or more dimensions.

In another exemplary embodiment, the imaging system can be configured as an ultrasonic imaging system that performs cross-sectional imaging of a first fluid. This system can perform multidimensional imaging by electronic or mechanical means to acquire one-, two-, or three-dimensional images of the sample as a function of time. In this exemplary embodiment the first fluid can be ultrasonically coupled to the imaging system in order to collect the radiation scattered from the first fluid that is collected by a detector. In the present exemplary embodiment, the imaging system can be configured to deliver a second fluid with different ultrasonic scattering properties onto the flow of the first fluid. In the present exemplary embodiment, the imaging system can be further configured to perform an analysis of the scattered ultrasonic radiation to determine the flow velocity of the first fluid.

According to certain exemplary embodiments of the present disclosure, an exemplary method for the measured data analysis on the detected radiation will provide a flow velocity of the first, second, or more fluids.

According to certain exemplary embodiments of the present disclosure, still another exemplary method for the measured data analysis on the detected radiation will provide a flow rate of the first, second, or more fluids.

In another embodiment, an apparatus including: an imaging system; a probe for insertion into a vessel, the probe being coupled to the imaging system; a flow delivery system associated with the probe to release a differential-contrast fluid into the vessel at a location proximal to an end of the probe; and a processor to: collect data from the imaging system based on release of the differential-contrast fluid into the vessel, analyze the collected data to identify a presence or absence of the differential-contrast fluid as a function of time, and determine a flow rate in the vessel based on analyzing the collected data.

In yet another embodiment, a method including: controlling a flow delivery system associated with a probe to cause release of a differential-contrast fluid into a vessel adjacent to the probe, the probe being optically coupled to an imaging system; collecting, using a processor, data from the imaging system based on the release of the differential-contrast fluid into the vessel; analyzing, using the processor, the collected data to identify a presence or absence of the differential-contrast fluid as a function of time; and determining, using the processor, a flow rate in the vessel based on analyzing the collected data.

The foregoing and other aspects and advantages of the present disclosure will appear from the following description. In the description, reference is made to the accompanying drawings that form a part hereof, and in which there is shown by way of illustration one or more exemplary versions. These versions do not necessarily represent the full scope of the invention.

Before any embodiments of the invention are explained in detail, it is to be understood that the invention is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the attached drawings. The invention is capable of other embodiments and of being practiced or of being carried out in various ways. Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. For example, the use herein of “including,” “comprising,” or “having” and variations thereof is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

1 FIG.A 1 FIG.B 1 FIG.A 1 FIG.A 4 FIG. 100 100 154 102 102 104 100 120 106 120 120 shows an embodiment of a systemfor obtaining flow rate information. The systemmay include a probe (e.g. optical probe, see) which may be disposed within a sleeve. The sleevein turn may be inserted through a guide catheter(). The systemmay include a fluid sourceassociated with the probe, for example through a Y-coupler(; see also). The fluid sourcemay be manually operated (e.g. a syringe) and/or may include a mechanical pump/power injector to deliver a fluid to a location proximal to an end of the probe. In certain embodiments, the probe may be inserted into a vessel such as a blood vessel (e.g. a coronary artery) and the fluid sourcemay be part of a flow delivery system to deliver a differential-contrast (or differential-scattering) fluid to the vessel; the rate of clearance of the fluid from the vessel can then be measured to determine a flow velocity and/or a flow rate for the vessel. In particular the flow velocity information can be combined with information regarding the cross-sectional area of the vessel to determine an absolute flow rate.

120 106 In certain embodiments, the flow delivery system includes the fluid source, which includes the fluid propulsion mechanism (e.g. syringe, pump, or other device for propelling fluid through the system), along with suitable tubing an connectors (including in some cases a Y-coupler) to deliver fluid to a vessel of interest in a controlled manner (e.g. controlled in one or more of timing, duration, and/or amount). The flow delivery system includes tubing that leads to release of the fluid at a point that is proximal to the probe end, for example from a guide catheter and/or a sleeve associated with the probe.

100 130 110 110 110 140 120 130 1 FIG.B In various embodiments, the systemmay also include a rotary junctionto rotatably couple the probe to an imaging device. The imaging devicemay include an interferometric system, such as a spectral domain optical coherence tomography (SD-OCT) system or an optical frequency domain imaging (OFDI) system and the probe an OCT probe as shown inand discussed further below. The imaging devicemay be coupled to and controlled by a computing device(described further below), which may in turn be coupled to and control one or both of the fluid sourceand the rotary junction.

1 FIG.B 1 FIG.A 154 152 152 156 160 154 110 130 In embodiments of the invention, the probe may include elements required for collection of data such as image data. For optical imaging embodiments, the probe may include elements such as one or more optical fibers which may have one or more optical components at the end thereof, such as lens(es) or mirror(s). In the embodiment shown in, the probeincludes optical fiber(s) which have an optical componentsuch as a ball lens at the distal end thereof. In general, the optical componentdirects a light beamat an angle θ (measured relative to the axis of the fiber(s)) towards a perimeter of the vesselto collect data. The proximal end of the optical fiber(s) of the probemay be optically coupled to the imaging devicevia the rotary junction() to facilitate collection of cross-sectional data from the vessel.

154 In certain embodiments, the probemay be inserted into a vessel such as a blood vessel through which blood is flowing such that the direction of blood flow is away from the end of the probe. A fluid (e.g. a differential-contrast/differential-scattering fluid) may be released into the vessel by the fluid source at a location that is proximal to the end of the probe, i.e. closer to the operator, so that the released fluid is carried by the blood flow towards and past the probe. As the released fluid moves past the probe, the probe is controlled to collect cross-sectional image data during time periods, e.g. 30 msec or less, and the cross-sectional data may then be analyzed to determine the flow velocity and flow rate within the vessel.

154 152 102 104 104 202 102 214 214 102 214 102 2 FIG.A 2 FIG.B In one embodiment, the probe(with optical componentat a distal end thereof) may be disposed within a sleevewhich in turn may be inserted through a guide catheter(); the guide cathetermay be used to deliver differential-contrast (or differential-scattering) fluid to the vessel, e.g. through opening. Alternatively, or in addition, in various embodiments the sleevemay include one or more openingsthrough which differential-contrast (or differential-scattering) fluid may be delivered to the vessel (). There may be 1, 2, 3, 4, or any suitable number of openingsin the sleeveand the openingsmay be located at the same position or at staggered locations along the sleeve.

154 102 102 222 102 222 224 222 154 104 2 FIG.C 2 FIG.C In still further embodiments, the probemay be disposed within the sleeve, which is an inner sleeve, and the (inner) sleevemay in turn be inserted within an outer sleeve(). In this case, the fluid may be delivered in the space between the innerand outersleeves and the openingsfor fluid release may be located on the outer sleeveto keep the fluid separate from the probe. In certain embodiments the double-sleeve device shown inmay in turn be fed through a guide catheter. In general, the sleeves are made from an optically transparent material to facilitate imaging through the sleeves.

302 304 104 302 102 306 304 302 104 306 304 3 3 FIGS.A,B 3 FIG.A 3 FIG.B 3 3 FIGS.A,B 3 3 FIGS.A andB 3 3 FIGS.C andD 3 FIG.D 3 3 FIGS.A-D In use, the probe may be inserted into a vesselsuch as a coronary artery where fluidis released and measured (). In some instances a guide cathetermay be inserted into a larger-diameter portion of the vesseland the probe (which may be inserted into a sleeve) may be guided into a smaller-diameter branch of the vessel, as shown inand in close up in insetin. Once the distal end of the probe has been placed in a suitable location for gathering data, the differential-contrast (or differential-scattering) fluidmay be released and the movement of the fluid through the branch of the vesselmay be monitored by the probe to determine a flow velocity/flow rate of the branch (). As shown in, the fluid may be released from the guide catheteror, as shown in, the fluid may be released from one or more openings in the sleeve associated with the probe (as shown in insetin). As discussed further below, data (e.g. cross-sectional images of scattering) collected by the probe before, during, and/or after release of the fluidmay be used to determine flow velocity/flow rate of blood in the vessel branch; the direction of blood flow inis indicated by arrows within the vessels.

4 FIG. 1 FIG.A 106 106 106 402 404 104 102 102 106 404 104 102 shows an embodiment of a Y-couplersuch as that shown in. The Y-couplermay be part of a flow delivery system which is used to release differential-contrast (or differential-scattering) fluid into a vessel. The Y-couplermay include a bodyand a side branchwhich may connect to a fluid delivery mechanism (e.g. a manual device such as a syringe or an automatic/mechanical device such as a pump) to deliver fluid to the guide catheterand/or sleeve, while the probe and/or sleevemay run straight through the Y-coupler. The side branchmay be fluidly connected to the guide catheterand/or the sleeveto deliver the fluid.

110 1 FIG.A 5 FIG.A 5 FIG.B 5 5 FIGS.A andB In various embodiments, the imaging deviceofmay be an interferometric imaging system such as an optical frequency domain imaging (OFDI) system () or a spectral-domain optical coherence tomography (SD-OCT) system (). Althoughare depicted using wave-guiding components, in other embodiments these systems can be constructed using free-space optics or combinations of wave-guides and free-space optical components.

5 FIG.A 510 560 500 560 500 500 500 575 500 540 500 575 500 500 570 500 520 500 570 500 a a a b c b g g h c m m i. shows an embodiment of an exemplary OFDI imaging system including a wavelength-swept sourcewhich provides an electromagnetic signal to the multiport coupler. This coupler can be a beam splitter, as is generally known in the art. The radiation propagates through the radiation coupling, which can consist of free-space components or of wave-guiding components. After coupler, radiation is separated in two couplingsand, which make up the sample and reference arm, respectively. Radiation going into couplingis sent into element, which can be a beam splitter or a circulator, as is known in the art. Couplingprovides radiation to the reference reflection, which is coupled back into the system via elements,, and. Similarly, radiation going into couplingis sent into element, which can be a beam splitter or a circulator, as is known in the art. Couplingprovides radiation to the samplethrough and endoscopic probe, which is coupled back into the system via,, and

560 550 520 540 550 580 520 b In operation of the OFDI system, sample light mixes with light from the reference reflection in the multiport coupler, and is sent to detector assemblyvia one or multiple couplings, depending on the use of single detectors, balanced detectors or with a system designed for polarization sensitive detection. Elementcan be fitted with means to perform multidimensional imaging, such as lenses or scanning systems. The reference reflectioncan have means to change the effective optical path length as is known in the art. Signal from detector assemblyis digitized by the digitizer. Due to the coherent mixing of the signals, by appropriate measurement schemes as are known in the art, it is possible to determine both the amplitude and phase of the radiation reflected from sampleas a function of depth, i.e. to perform cross-sectional imaging.

520 520 Other implementations of the light coupling and scanning systemare also possible. Specifically, in the case of OFDI systems used in cardiovascular applications, systemis generally configured in the form of a catheter. The sample in cardiovascular applications can be blood inside a vessel. A scanning system based on a catheter performs one-dimensional measurements of the reflectance of the sample with depth (known as A-lines) and mechanical rotation allows for scanning of the transverse plane. At the same time the catheter can be “pulled-back” to provide sectioning along the longitudinal direction to gather three-dimensional data from the sample. However, in the particular embodiments disclosed herein, the imaging probe is generally maintained in a single location, continuously imaging the same spot, to obtain information about the fluid moving through the vessel.

5 FIG.B 5 FIG.A 510 560 550 550 a shows an exemplary spectral-domain optical coherence tomography system consisting of a broadband sourceB which provides an electromagnetic signal to the multiport coupler. This coupler can be a beam splitter, as is generally known in the art. The rest of the system is analogous to that in, except for the detection stage, which includes a spectral detector and digitizersB. In various embodiments, spectral detector and digitizersB may include a spectrometer with associated camera and signal digitization. In various embodiments, other interferometric imaging modalities may be used in place of OFDI or SD-OCT, such as time domain OCT or circular ranging OCT.

1 FIG.A 5 FIG.C 1 FIG.B 610 650 600 600 620 600 630 600 640 620 154 152 a b c d In other embodiments, an ultrasound (e.g. intravascular ultrasound, or IVUS) probe (e.g. associated with a fluid delivery system as in) may be inserted into a vessel and used to track clearance of a fluid from the vessel.shows an exemplary ultrasound imaging system which includes an ultrasonic pulse generator/beamformer/amplifier system, which provides an electrical signal to the transmitter/receiver switch. The electrical signal propagates through the electrical coupling, which can include a single cable or an array of electrical cables. Couplingtransmits/receives signal to/from the endoscopic transducer. Couplingtransmits the electrical signal to the receiver/amplifier/beamformer, which is then connected through couplingto the data acquisition and processing unit. With reference to other figures herein which depict optical modalities, the endoscopic transducerserves an analogous purpose to the probeand optical component(see as in) as least with regard to directing energy which is used to generate a cross-sectional image of the vessel.

5 FIG.D 710 700 720 700 710 720 700 710 730 700 740 730 710 740 740 a a b c In still other embodiments, fluoroscopy, MRI, or CT may be used to monitor a vessel and track clearance of a differential-contrast (or differential-scattering) fluid as disclosed herein. For non-invasive imaging modalities such as these, a catheter or other probe mechanism may be inserted into a vessel to deliver a fluid in a particular location in a controlled manner, while imaging of the fluid delivery and clearance may be conducted non-invasively by the imaging system.shown an exemplary embodiment of the present invention using a generic non-invasive imaging modality. The fluid source and delivery systemis coupled through connectionwith the endoscopic fluid delivery system. Connectionis a fluid delivery connection and may, in some embodiments, also be used to deliver electrical signals to manipulate distal elements of the fluid delivery systemthat are present in the endoscopy fluid delivery probe. Electrical connectionconnects the fluid source and delivery systemwith computing device, which is then connected through electrical connectionto the standard non-invasive imaging system. Computing devicecoordinates the fluid delivery systemwith a non-invasive imaging system, and can manipulate parameters related to both the fluid delivery and the image acquisition process. The non-invasive imaging systemmay include at least one of a non-invasive ultrasound system (when measuring flow in a vessel accessible with such a system, e.g. the carotid), an Mill, a CT, and/or 2D and 3D fluoroscopy. Two-dimensional (2D) fluoroscopy can be used given some assumptions about vessel geometry, whereas three-dimensional (3D) fluoroscopy (fluoroscopy with more than one imaging plane) will necessitate fewer or no assumptions about vessel geometry.

1 1 2 2 FIG.A,B,A,B 1 FIG.A 5 FIG.D 2 120 104 102 Any of the imaging modalities disclosed herein may be used in conjunction with a flow delivery system as shown in, orC, for example delivering fluid from a fluid sourceunder control of a manual or automatic mechanism to deliver fluid through a guide catheterand/or a sleevehaving one or more openings therein. The flow delivery system may be associated with an imaging probe, as shown in, or may be a separate component that is operated in a coordinated fashion, as shown in(e.g. for use with non-invasive imaging modalities).

In general, a differential-contrast/differential scattering fluid is selected for the particular imaging modality that is used in order to provide a signal that is significantly different from blood. For interferometric imaging modalities such as OFDI or SD-OCT, blood cells provide scattering and therefore an added fluid that has a difference in scattering (higher or lower) than blood can be used to track the addition and clearance of the fluid and in turn provide a measure of flow through the vessel. The properties of the added fluid in other modalities will depend on how the modality detects blood and other fluids to provide differential contrast or scattering.

In some embodiments the fluid may have a lower signal than blood, e.g. saline, Ringer's lactate solution, dextran, or a radiopaque contrast media preferably an iodinated contrast media such as Visipaque or Omnipaque. In addition, a plurality of the kinds of the fluids may be blended. In particular embodiments, a blend of the radiopaque contrast media and saline is preferred. In other embodiments, the fluid may have a higher signal than blood, e.g. a lipid emulsion such as Intralipid (e.g. at concentrations between 1-5%), a microbubble-based solution, or one or more scattering particles (micro-spheres, micro-beads, nano-particles such as nano-rods, nano-clusters, nano-powders, etc.) which may be diluted in any of the above-listed clear media (e.g. saline, Ringer's lactate solution, dextran, or a radiopaque contrast media preferably an iodinated contrast media such as Visipaque or Omnipaque). The particular fluid that is selected is based on the imaging modality: for optical imaging including OCT and related modalities, fluids such as saline, Ringer's lactate solution, or dextran solutions may be used; for US based modalities, fluids such as microbubble-based solutions or solutions based on scattering particles may be used; for modalities such as fluoroscopy or CT, radiopaque agents such as iodinated contrast fluids including Visipaque or Omnipaque may be used; and for Mill modalities, fluids containing magnetic agents such as superparamagnetic or paramagnetic contrast agents (e.g. gadolinium) may be used.

5 5 FIGS.A andB In various embodiments, the differential-contrast (or differential-scattering) fluid is released into the vessel at a location that is “upstream” (relative to the flow direction in the vessel) of the location where measurements are made. For an imaging probe such as that shown in, fluid is released at a location that is “proximal” relative to the end of the probe, meaning in the direction of the user or operator of the probe. In contrast, the “distal” end of the probe is the end furthest from the user or operator and generally where imaging occurs. The distance between the location of fluid release and the location of imaging may vary but is generally in a range of 1 mm-10 mm, with longer distances being preferable. In various embodiments, a volume of fluid in a range of 0.1 mL to 10 mL may be released into vessel over a period of 0.1 sec to 10 sec, depending on the diameter of the vessel and the estimated flow rate of the vessel. In general, the volume may be smaller than, similar to, or larger than the volume of sample flowing per flushing time. In cases where a larger volume of fluid is delivered, the flushing time should generally be kept short so as to not substantially alter the flow rate of the sample.

In particular embodiments, the imaging modality (e.g. OCT, US, MRI, CT, or fluoroscopy) has sufficient spatial resolution so as to obtain at least about 10 samples across the inner diameter of the vessel, i.e. the modality generally has a minimum resolution of about 1/10th the inner diameter of the vessel. Thus, a cross-sectional sample through a vessel may contain an array of 10×10 voxels or pixels of data. For a vessel such as a coronary artery having an inner diameter anywhere in a range of 2.0-5.0 mm, the minimum resolution needed to obtain a 10×10 array of samples would be in a range of 0.2-0.5 mm, although using a modality with higher resolution and/or a greater number of samples is also possible. Having at least a 10×10 array of data through the cross-sectional sample helps provide sufficient data to track clearance of the added fluid with fine enough resolution to properly estimate parameters such as flushing time (see below) and vessel diameter, which in turn may be used to determine flow velocity and flow rate.

In general, data may be collected before, during, and after release of differential-contrast/differential-scattering fluid into the vessel. The data is generally from a single location in the vessel, typically a cross-sectional area, and is used to track clearing of the fluid from the vessel based on the difference in signal between the fluid and blood. Data is collected during a series of time periods to develop a time course, where the time periods may range from 1 msec to 30 msec and in general are 30 msec or less. Data from each time period (e.g. an image frame) processed to identify a fraction of the vessel's area that is occupied by fluid or blood. In some embodiments, image data may be thresholded (e.g. based on a minimum signal level associated with the presence of blood, and which consistently show this signal for a particular number of successive frames) in order to identify pixels which contain either fluid or blood.

−1 In the case of two-dimensional cross-sectional image data, the result of the analysis may be to provide a fractional area of the vessel at each data point that has fluid. A normalized time course (e.g. data from each successive frame) of the fractional area (flushed area) can then provide an indication of the time course of flushing, which in turn indicates flow velocity in the vessel. Flow velocity can be combined with the cross-sectional area of the vessel to identify the absolute flow rate of the vessel. In some embodiments, a simpler analysis involves tracking frame mean intensity to identify the time course of flushing, although the results may be noisier than those based on the flushed area. Data based on the flushed area can be used to identify a flushing time τ which is defined as the time when the normalized flushed area reaches 0.5 and, in the Example described below, the inverse of the flushing time (τ) exhibited a linear relationship with flow rate.

Identify the vessel lumen and define the area that carries the flow of interest; Determine a threshold value that will be used to determine whether a given pixel in the image contains sample fluid or injectate. If the injectate has weaker scattering than the sample, the threshold will be implemented as a comparison of the form I>threshold, while if the injectate has stronger scattering the threshold will be implemented as a comparison of the form I>threshold; Determine a minimum number of frames N that are required to consider a specific pixel as fully flushed; Perform the threshold comparison on a frame-by-frame basis and assemble a collection of images showing flushed area as a function of time; A further exemplary embodiment of the present invention might transform the image intensity into a radiation attenuation coefficient or a similar metric, as is known in the art, before performing the analyses as explained in the present invention. An exemplary embodiment to determine the flow rate in the vessel of interest is as follows:

The average intensity of the vessel lumen as a function of time can be used to assess the signal-to-noise ratio of the measurement, by analyzing the modulation depth on the mean intensity of the image as the bolus passes; By calculating the total area of the vessel lumen, it is possible to determine the normalized flushed area as a function of time; The flushing time can be defined as the time it takes for 50% of the lumen area to be flushed, and can be readily calculated from the normalized flushed area as a function of time; The inverse of the flushing time is proportional to the flow velocity. A calibration can be performed to determine the proportionality constant. Another exemplary embodiment for determining the flow velocity from the flushed area is as follows:

Calculate the area of the vessel lumen from the image; Calculate the product of the area times the flow velocity as calculated according to the present invention; Yet another exemplary embodiment to determine the flow rate in the vessel of interest is as follows:

Calculate the average intensity of the vessel lumen as a function of time; Identify the frame during the bolus passage with the most homogeneous intensity in the lumen area; The average intensity of this frame is directly related to the flow rate of the sample and the ratio of backscattering between the sample and injectate. This relation can be calibrated and used during measurements of unknown flow rates. A further exemplary embodiment for determining the flow velocity from the flushed area, when there is complete delivery of the injectate, is as follows:

6 6 7 8 8 9 FIGS.A,B,,A,B, and describe a non-limiting Example of the disclosed blood flow quantification technique based on a backscattering indicator-dilution approach, in particular using intravascular optical coherence tomography (IV-OCT). In this Example, the flow velocity is determined in a coronary artery of interest by analyzing the backscattering signal from blood after passage of a bolus of Ringer's lactate or another transparent injectate. In contrast to other techniques such as thermodilution CFR the structural OCT image can be used to determine the bolus volume and transit time, thus enabling the determination of absolute coronary flow rates with standard OCT systems. If used in conjunction with thermodilution CFR, the collected OCT images can also be used to account for motion and volume change between the two CFR flow readings, potentially improving CFR accuracy.

A small bolus (~1 mL) of transparent injectate was delivered in a short time period, fully displacing the blood as it is regularly seen during traditional OCT imaging. The time it takes for the injectate to fully disappear from the cross-sectional view (and therefore for blood to fill the vessel lumen) is proportional to the flow velocity. Once the flow velocity has been determined, the cross-sectional lumen area from the OCT image can be used to determine the absolute blood flow rate.

6 6 FIGS.A,B An intravascular (IV) OCT system (wavelength-swept laser centered at 1300 nm, 105 nm bandwidth, 54 kHz repetition rate) was used for the experiments presented in this Example. A standard guide catheter was used with an IV-OCT catheter, and imaging was performed at 3 cm from the guide catheter at 50 fps. In this Example, the guide catheter was used to flush transparent injectate into the simulated vessel. The simulated vessel () was part of a simulated vascular system and was coupled to a fluid reservoir, a peristaltic pump, a pulse dampener, and a return reservoir. A syringe filled with injectate (e.g. saline) was coupled to the IV-OCT catheter to permit introduction of the fluid into the system upstream of the probe.

6 6 FIGS.A,B The simulated vessel contained a 2% solution of Intralipid as a blood phantom flowing in an open circuit (). Simulated flow rates of 17, 30, 43, and 57 mL/min were generated, corresponding to peak flow velocities of 70, 130, 190, and 250 mm/s in the 3.1 mm diameter section of tube into which the IV-OCT probe was inserted.

7 FIG. The OCT probe was coupled to a rotary junction, permitting the probe to continuously rotate while collecting interferometric information. During experiments, the probe was rotated while fluid was released into the vessel and a series of Bscans were obtained from a fixed location in the simulated vessel. Each B scan, which uses polar coordinates, was converted into a 512×512 pixel image with Cartesian coordinates, which was then cropped to define a 200×200 pixel luminal region of interest which included the lumen of the simulated vessel ().

7 FIG. 7 FIG. 3 10 20 40 Data in the luminal region of interest was segmented for each frame, starting from the frame of minimum average intensity, i.e. the frame representing the initial bolus of injectate having the lowest scattering. For these experiments, pixels having moderate intensity (e.g. >15 dB over noise floor) for 5 or more frames were considered flushed of “blood” (i.e. Intralipid solution). Next, the fraction of flushed pixels (corresponding to the fractional area) was calculated for each frame.shows a series of frames (frame nos.,,, andas indicated at the bottom of) at flow rates of 17 mL/min and 57 mL/min. The bottom row in each group is the structural information for each frame and the top row shows the segmented data showing the flushed area (which recovers from the first to last frame of each group).

8 FIG.A 8 FIG.B 8 FIG.B 9 FIG. −1 shows the mean frame intensity for data obtained at each of the flow rates; this data shows that mean frame intensity provides a general indication of adequate flushing but is too noisy for accurate flow determination.shows that the normalized flushed area is robust and exhibits clearly differentiated behavior for different flow rates. Based on data such as that shown in, the flushing time τ is defined as the time when the normalized flushed area reaches 0.5. As shown in, the inverse flushing time τexhibits a linear relationship with flow rate.

This Example shows that the disclosed techniques, which combine a straightforward flushing technique with a simplified analysis regime and which are compatible with standard OCT imaging, are capable of measuring absolute flow rates in vitro. The catheter (0.8 mm diameter) corresponds to an area stenosis of <10% in a 3 mm diameter segment, which is unlikely to decrease measured blood flow; thus the presence of the probe in the vessel does not adversely impact flow rates. Furthermore, the access to structural image information that this technique provides could make this technique more accurate than other methods such as thermo-CFR by accounting for vessel diameter and catheter location changes.

10 FIG. 1000 1010 1000 1020 1000 1030 1000 1040 1000 shows a flow chart of a methodfor determining a flow rate. In, the methodprovides for controlling a flow delivery system associated with a probe to cause release of a differential-contrast fluid into a vessel adjacent to the probe, where the probe is optically coupled to an imaging system. Inthe methodprovides for collecting, using a processor, data from the imaging system based on the release of the differential-contrast fluid into the vessel. Inthe methodprovides for analyzing, using the processor, the collected data to identify a presence or absence of the differential-contrast fluid as a function of time. Finally, inthe methodprovides for determining, using the processor, a flow rate in the vessel based on analyzing the collected data.

140 110 120 130 1100 110 140 1110 1112 1114 1118 1120 1122 1126 1126 1112 1114 11 FIG. 11 FIG. 11 FIG. In various embodiments, the computing devicemay be operably connected to one or more of the imaging device, the fluid source, or the rotary junctionto facilitate collection and analysis of data. Thus,shows an exampleof hardware that can be used to implement an imaging device and/or a computing device that can be used in connection with some embodiments of mechanisms for determining intravascular blood flow using a backscattering contrast in accordance with some embodiments of the disclosed subject matter. For example, hardware shown incan be used to implement at least a portion of spectrometer imaging deviceand/or computing device. As shown in, in some embodiments, an imaging systemcan include a hardware processor, a user interface and/or display, one or more communication systems, memory, one or more light sources, one or more electromagnetic detectors, and/or one or more optical connectors. In some embodiments, hardware processorcan be any suitable hardware processor or combination of processors, such as a central processing unit (CPU), a graphics processing unit (GPU), a microcontroller (MCU), a field programmable gate array (FPGA), a dedicated image processor, etc. In some embodiments, input(s) and/or displaycan include any suitable display device(s), such as a computer monitor, a touchscreen, a television, a transparent or semitransparent display, a head mounted display, etc., and/or input devices and/or sensors that can be used to receive user input, such as a keyboard, a mouse, a touchscreen, a microphone, a gaze tracking system, motion sensors, etc.

1118 1102 1118 1118 In some embodiments, communications systemscan include any suitable hardware, firmware, and/or software for communicating information over a communication networkand/or any other suitable communication networks. For example, communications systemscan include one or more transceivers, one or more communication chips and/or chip sets, etc. In a more particular example, communications systemscan include hardware, firmware and/or software that can be used to establish a Wi-Fi connection, a Bluetooth connection, a cellular connection, an Ethernet connection, an optical connection, etc.

1102 1102 1102 11 FIG. In some embodiments, communication networkcan be any suitable communication network or combination of communication networks. For example, communication networkcan include a Wi-Fi network (which can include one or more wireless routers, one or more switches, etc.), a peer-to-peer network (e.g., a Bluetooth network), a cellular network (e.g., a 3G network, a 4G network, etc., complying with any suitable standard, such as CDMA, GSM, LTE, LTE Advanced, WiMAX, etc.), a wired network, etc. In some embodiments, communication networkcan be a local area network, a wide area network, a public network (e.g., the Internet), a private or semi-private network (e.g., a corporate or university intranet), any other suitable type of network, or any suitable combination of networks. Communications links shown incan each be any suitable communications link or combination of communications links, such as wired links, fiber optic links, Wi-Fi links, Bluetooth links, cellular links, etc.

1120 1112 1114 1130 1118 1120 1120 1120 1110 1112 1130 In some embodiments, memorycan include any suitable storage device or devices that can be used to store instructions, values, etc., that can be used, for example, by hardware processorto process image data generated by one or more optical detectors, to present content using input(s)/display, to communicate with a computing devicevia communications system(s), etc. Memorycan include any suitable volatile memory, non-volatile memory, storage, any other suitable type of storage medium, or any suitable combination thereof. For example, memorycan include RAM, ROM, EEPROM, one or more flash drives, one or more hard disks, one or more solid state drives, one or more optical drives, etc. In some embodiments, memorycan have encoded thereon a computer program for controlling operation of imaging system. In some such embodiments, hardware processorcan execute at least a portion of the computer program to control one or more light sources and/or detectors (e.g., to capture OCT data as described herein), to generate images and/or calculate values (e.g., an OCT image, etc.), transmit and/or receive information to/from computing device, etc.

1110 1122 1122 1122 1122 5 FIG.A 5 FIG.B In some embodiments, imaging systemcan include one or more light sources, such a coherent or incoherent light source (e.g., a light emitting diode or combination of light emitting diodes, a white light source, etc.), which can be a broadband light source, or a narrower band light source. For example, light sourcecan be a wavelength-swept source as described above in connection with. As another example, light sourcecan be a broadband source as described above in connection with. Additionally, in some embodiments, light sourcescan be associated with one or more filters.

1110 1124 1124 In some embodiments, imaging systemcan include one or more light detectors, such as one or more photodiodes, and/or one or more image sensors (e.g., a CCD image sensor or a CMOS image sensor, either of which may be a linear array or a two-dimensional array). For example, in some embodiments, detectorscan include one or more detectors configured to detect light at specific wavelengths (e.g., using filters, using optics to guide light of different wavelengths to different portions of the detector(s), etc.)

1110 1126 1122 1124 In some embodiments, imaging systemcan include one or more optical connectors. For example, such optical connectors can be fiber optic connectors configured to form an optical connection between light source(s)and/or detectorand an optical fiber (e.g., as part of a fiber optic cable).

1130 1132 1134 1136 1138 1140 1132 1134 1136 In some embodiments, computing devicecan include a hardware processor, a display, one or more inputs, one or more communication systems, and/or memory. In some embodiments, hardware processorcan be any suitable hardware processor or combination of processors, such as a CPU, a GPU, an MCU, an FPGA, a dedicated image processor, etc. In some embodiments, displaycan include any suitable display devices, such as a computer monitor, a touchscreen, a television, a transparent or semitransparent display, a head mounted display, etc. In some embodiments, inputscan include any suitable input devices and/or sensors that can be used to receive user input, such as a keyboard, a mouse, a touchscreen, a microphone, a gaze tracking system, motion sensors, etc.

1138 1102 1138 1138 In some embodiments, communications systemscan include any suitable hardware, firmware, and/or software for communicating information over communication networkand/or any other suitable communication networks. For example, communications systemscan include one or more transceivers, one or more communication chips and/or chip sets, etc. In a more particular example, communications systemscan include hardware, firmware and/or software that can be used to establish a Wi-Fi connection, a Bluetooth connection, a cellular connection, an Ethernet connection, etc.

1140 1132 1134 1140 1140 1140 1130 1132 1110 In some embodiments, memorycan include any suitable storage device or devices that can be used to store instructions, values, etc., that can be used, for example, by hardware processorto present content using display, to communication with one or more imaging devices, etc. Memorycan include any suitable volatile memory, non-volatile memory, storage, any other suitable type of storage medium, or any suitable combination thereof. For example, memorycan include RAM, ROM, EEPROM, one or more flash drives, one or more hard disks, one or more solid state drives, one or more optical drives, etc. In some embodiments, memorycan have encoded thereon a computer program for controlling operation of computing device. In such embodiments, hardware processorcan execute at least a portion of the computer program to receive content (e.g., image content) from one or more imaging devices (e.g., imaging device), present content (e.g., images and/or values) transmit content to one or more other computing devices and/or imaging systems, etc.

1130 1130 1130 In some embodiments, computing devicecan be any suitable computing device, such as a general purpose computer or special purpose computer. For example, in some embodiments, computing devicecan be a smartphone, a wearable computer, a tablet computer, a laptop computer, a personal computer, a server, etc. As another example, in some embodiments, computing devicecan be a medical device, a system controller, etc.

In some embodiments, any suitable computer readable media can be used for storing instructions for performing the functions and/or processes described herein. For example, in some embodiments, computer readable media can be transitory or non-transitory. For example, non-transitory computer readable media can include media such as magnetic media (such as hard disks, floppy disks, etc.), optical media (such as compact discs, digital video discs, Blu-ray discs, etc.), semiconductor media (such as RAM, Flash memory, electrically programmable read only memory (EPROM), electrically erasable programmable read only memory (EEPROM), etc.), any suitable media that is not fleeting or devoid of any semblance of permanence during transmission, and/or any suitable tangible media. As another example, transitory computer readable media can include signals on networks, in wires, conductors, optical fibers, circuits, any other suitable media that is fleeting and devoid of any semblance of permanence during transmission, and/or any suitable intangible media.

Thus, while the invention has been described above in connection with particular embodiments and examples, the invention is not necessarily so limited, and that numerous other embodiments, examples, uses, modifications and departures from the embodiments, examples and uses are intended to be encompassed by the claims attached hereto.